3-Acetyl-1,4-dihydro-4-oxo-1,8-naphthyridines

ABSTRACT

Process of reacting 2-amino-6-Q&#39;&#39;-pyridine (I) with lower-alkyl (lower-alkoxy)methyleneacetoacetate (II) to produce lower-alkyl Alpha -(6-Q&#39;&#39;-2-pyridylaminomethylene)acetoacetate (III&#39;&#39;), heating lower-alkyl Alpha -(6-Q-2-pyridylaminomethylene)acetoacetate (III), to produce 3-acetyl-1,4-dihydro-7-Q-4-oxo-1,8naphthyridine (IV) which is tautomeric with 3-acetyl-4-hydroxy-7Q-1,8-naphthyridine (IVA), reacting IV (or IVA) with a loweralkylating agent to produce 3-acetyl-1-(lower-alkyl)-1,4-dihydro7-Q-4-oxo-1,8-naphthyridine (V) and converting V to 1-(loweralkyl)-1,4-dihydro-7-Q-4-oxo-1,8-naphthyridine-3-carboxylic acid (VI), where Q is lower-alkyl, hydroxymethyl, loweralkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)-pyridyl having one or two lower-alkyl substituents, and Q&#39;&#39; is like Q but excluding lower-alkanoyloxymethyl. The compounds of formula VI are known antibacterial agents. Also given are alternative routes of preparing III and IV where Q is lower-alkanoyloxymethyl by reacting the N-oxides of III and IV, respectively, where Q is methyl with a lower-alkanoic acid anhydride.

United States Patent [191 Lesher et al.

[4 1 Dec. 9, 1975 3-ACETYL-1,4-DlHYDRO-4-OXO-l,8-

NAPHTHYRIDINES [75] Inventors: George Y. Lesher; Ruth Pauline Brundage, both of Rensselaer, NY.

[73] Assignee: Sterling Drug Inc., New York, NY.

[22] Filed: Nov. 1, 1974 [21] Appl. No.: 520,135

Related US. Application Data [62] Division of Ser. No. 453,928, March 22, 1974, Pat. No. 3,895,017, which is a division of Ser. No. 333,541, Feb. 20, 1973, Pat. No. 3,875,172

[52] US. Cl. 260/296 N; 260/295 N [51] Int. Cl. C07D 471/04 [58] Field of Search 260/295 N, 296 N [56] References Cited UNlTED STATES PATENTS 3,873,554 3/1975 Lesher et al. 260/296 N Primary ExaminerJohn D. Randolph Assistant ExaminerBernard I. Dentz Attorney, Agent, or Firm-Robert K. Bair; B. Woodrow Wyatt 57 ABSTRACT Process of reacting 2-amino-6-Q'-pyridine (I) with lower-alkyl (lower-alkoxy)methyleneacetoacetate (II) to produce lower-alkyl a-(6-Q'-2-pyridylaminomethylene)acetoacetate (III), heating lower-alkyl a-(6- Q-2-pyridylaminomethylene)acetoacetate (III), to produce 3-acetyl-l ,4-dihydro-7-Q-4-oxo-1 ,8- naphthyridine (IV) which is tautomeric with 3-acetyl- 4-hydroxy-7-Q-1,8-naphthyridin (IVA), reacting IV (or IVA) with a lower-alkylating agent to produce 3- acetyll lower-alkyl 1 ,4-dihydro-7-Q-4-oxo- 1 ,8- naphthyridine (V) and converting V to l-(loweralkyl)-l ,4-dihydro-7-Q-4-oxol ,8-naphthyridine-3- carboxylic acid (VI), where Q is lower-alkyl, hydroxymethyl, lower-alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)-pyridyl having one or two lower-alkyl substituents, and Q is like Q but excluding loweralkanoyloxymethyl. The compounds of formula VI are known antibacterial agents. Also given are alternative routes of preparing III and IV where Q is loweralkanoyloxymethyl by reacting the N-oxides of III and IV, respectively, where Q is methyl with a loweralkanoic acid anhydride.

4 Claims, N0 Drawings 3-ACETYL-1,4-DII'IYDRO-4-OXO-1,8-NAPHTHYRI- DINES This application is a division of co-pending application Ser. No. 453,928, filed Mar. 22, 1974 and now US. Pat. No. 3,895,017, issued July 15, 1975, which in turn is a division of co-pending application Ser. No. 333,541 filed Feb. 20, 1973 and now US Pat. No. 3,875,172, issued Apr. 1, 1975. This invention relates to steps in the process of preparing l ,S-naphthyridine3-carboxylic acids and to compositions used therein.

The invention in a process aspect comprises the four steps of reacting 2-amino-6-Q-pyridine (l) with loweralkyl (lower-alkoxy)methyleneacetoacetate (II) to produce lower-alkyl a-(6-Q-2-pyridylaminomethylene)acetoacetate (III'), heating lower-alkyl a-(6-Q-2- pyridylaminomethylene)acetoacetate (III), to produce 3-acetyl- 1 ,4-dihydro-7-Q-4- oxo- 1 ,S-naphthyridine (IV) which is tautomeric with 3-acetyl-4-hydroxy-7-Q- 1,8-naphthyridine (IVA), reacting IV (or IVA) with a lower-alkylating agent to produce 3-acetyl-1-(loweralkyl)-1,4-dihydro-7-Q-4-oxo- 1,8-naphthyn'dine (V) and converting V to 1-(lower-alkyl)-1,4-dihydro-7-Q- 4-oxo-l,8-naphthyridine-3-carboxylic acid (VI), where Q is lower-alkyl, hydroxymethyl, lower-alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)-pyridyl having one or two lower-alkyl substituents, and Q is like Q but excluding lower-alkanoyloxymethyl. The compounds of formula VI are known antibacterial agents. In addition to said combination of the four steps, other process aspects of the invention are each individual step and the consecutive combinations of two or three steps.

The invention in its composition aspects resides in the compounds: lower-alkyl oz-(6-Q-2- pyridylaminomethyleneacetoacetate of the formula 111 COCH N NHCH=C/ 3 COOR III

where R is lower-alkyl; 3-acetyl-l,4-dihydro-7-Q-4- oxo-l,8-naphthyridine and its tautomeric 3-acetyl-4- hydroxy-7-Q-l,8-naphthyridine of the respective formulas IV and IVA Q \N N IVA and 3-acety1-1-(lower-alkyl)-1,4-dihydro-7-Q4-oxo- 1,8-naphthyridine of the formula V where R is lower-alkyl and Q in each of the formulas III, IV, IVA and V is defined as hereinabove.

Preferred process and composition embodiments, because of high antibacterial activity of final products and ready availability of intermediates are those where Q is methyl, hydroxymethyl, acetoxymethyl, 4-pyridyl, 3- pyridyl, 2-methyl-4-pyridyl and 2,6-dimethyl-4-pyridyl, and Q is like Q but excluding acetoxymethyl.

Other process aspects of the invention comprise the steps of converting the compound of formula III or IV (or IVA) where Q is methyl, that is, lower-alkyl a-(6- methyl-2-pyridylaminomethylene)acetoacetate or 3- acetyl-l,4-dihydro-7-methyl-4 o x o-1,8-naphthyridine (or 3-acetyl-4-hydroxy-7-methyl-1,8-naphthyridine) to its 6-methyl-l-oxo-2 pyridyl derivative or 8- oxide, respectively, by reacting it with an agent capable of forming N-oxides and then reacting said l-oxo-Z- pyridyl compound or 8-oxide with a lower-alkanoic anhydride to produce the compound of formula III or IV (or IVA), respectively, where Q is lower-alkanoyloxymethyl. I

The term lower-alkyl, as used herein, e.g., as represented by R informula III, Q in formulas III, IV, IVA and V, or R in formula V, means alkyl radicals having from one to six carbon atoms which can be arranged as straight or branched chains, illustrated by methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, namyl, n-hexyl, and the like.

The term lower-alkoxy, as used herein, e.g., in the intermediate lower-alkyl (lower-alkoxy)methyleneacetoacetate (II), means alkoxy radicals having from one to six carbon atoms which can be arranged as straight or branched chains, illustrated by methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, isobutoxy, n-amoxy, n-hexoxy, and the like.

The term lower-alkanoyl, as used herein, e.g., in the definition of the Q substituent as lower-alkanoyloxymethyl in formulas III, IV, IVA and V, means alkanoyl radicals having from one to six carbon atoms, including the straightand branched-chained radicals, illustrated by formyl, acetyl, propionyl (propanoyl), butyryl '(butanoyl), isobutyryl (2-methylpropanoyl) and caproyl (hexanoyl).

Illustrative of the Q substituent in I or the Q substituent in formulas III, IV, IVA and V where Q or Q is 4(or 3)-pyridy1 having one or two lower-alkyl substituents are the following: 2-methyl-4-pyridyl, 2,6-dimethyl-4- pyridyl, 3-methyl-4-pyridyl, 2-methyl-3-pyridyl, 6- methyl-3-pyridyl (preferably named 2-methyl-5-pyridyl), 2,3 dimethyl-4-pyridyl, 2,5-dimethyl-4-pyridyl, 2-ethyl4-pyridyl, 2-isopropyl-4-pyridyl, 2-n-butyl-4- pyridyl, 2-n-hexyl-4-pyridyl, 2,6-diethyl- 4-pyridyl, 2,6-

diethyl-S-pyridyl, 2,6-diisopropyl-4-pyridyl, 2,6-dinhexyl-4-pyridyl, and the like. Because of ready availability, ease of preparation and/or high antibacterial activity of the final products, i.e., the l-(lower-alkyl)- 1,4- dihydro-7-[mono(or di)-(lower-alky])-4(or 3) pyridyl]-4-oxol,S-naphthyridine-3-carboxylic acids, preferred embodiments of this group are those where 4(or 3)-pyridyl is substituted by one or two methyl, especially the 2-methyl-4-pyridyl and 2,6-dimethyl-4- pyridyl compounds. Other preferred embodiments are those having unsubstituted-4(or 3)-pyridyl as Q.

As shown above, 3-acetyl-l,4-dihydro-7-Q-4-oxo- 1,8-naphthyridine of formula IV is tautomeric with 3- acetyl-4-hydroxy-7-Q-l,S-naphthyridine of formula IVA. As with all tautomeric systems, the rate of the transformation IV 7- IVA and the ratio IV/IVA are dependent on the thermodynamic environment, including the state of aggregation; so that-measurements by any particular techniques do not necessarily have validity except under the conditions of the measurement, thereby, among other consequences, giving rise to problems for any simple designation of the physical embodiments. Thus, measurements of the infrared spectra, in potassium bromide admixture, or in chloroform or mineral oil, indicate existence predominantly as IV and the names of the compounds herein therefore are preferably based on structure IV, although it is understood that either or both structures are comprehended.

The intermediate 2-amino-6-Q-pyridines (I) are either known or, where novel, are prepared from known compounds by conventional means as illustrated hereinbelow.

The molecular structures of the composition aspects (III, IV, IVA and V) of our invention were assigned on the basis of evidence provided by infrared, ultraviolet and nuclear magnetic resonance spectra, by chromatographic mobilities, and, by the correspondence of calculated and found values for the elementary analyses for representative examples.

The manner of making and using the instant invention will now be generally described so as to enable a person skilled in the art of chemistry to make and use the same, as follows:

The reaction of 2-amino-6-Q-pyridine (I) with lower-alkyl (lower-alkoxy)methyleneacetoacetate (II) to produce lower-alkyl a-(6-Q-2-pyridylaminomethylene )acetoacetate (III) is carried out by mixing the reactants (I and Il), preferably in a molar ratio of 1:1 and preferably with stirring, either in the absence or presence of a suitable inert solvent, at about room temperature (2025C.) to about 100C. Higher temperatures can be used but to no particular advantage. In some instances the reaction takes place exothermally. The reaction is conveniently run by mixing the reactants, preferably using ethyl ethoxymethyleneacetoacetate because of its ready availability and low cost, with stirring in a lower-alkanol, preferably ethanol, at room temperature and then warming the reaction mixture on a steam bath for a short period to ensure completion of the reaction. Other suitable solvents inert under the re action conditions include acetonitrile, dimethylformamide, benzene, and the like.

The reaction of lower-alkyl a-(6-Q-2-pyridylaminomethylene)acetoacetate (III) to produce 3-acetyl-l,4- dihydro- 7-Q-4-oxo-l,S-naphthyridine (IV) is carried out by heating III in an inert solvent at about 200325C., preferably at about 250-300C. Such solvents include mineral oil, diethyl phthalate, dibenzyl ether, nitrobenzene, the eutectic mixture of diphenyl and diphenyl ether (Dowtherm A), and the like.

4 Alternatively, the above two steps can be run consecutively without isolation of compound III.

The reaction of 3-acetyl-l,4-dihydro-7-Q-4-oxo-l ,8- naphthyridine (IV) or its tautomeric 3-acetyl-4- hydroxy-7-Q-l,S-naphthyridine (IVA) with a loweralkylating agent to produce 3-acetyl-l-(lower-alkyl)- 1,4-dihydro-7-Q-4-oxo-1,8-naphthyridine (V) is generally carried out by reacting said compound of formula IV or IVA with a lower-alkyl ester of a strong inorganic acid or an organic sulfonic acid, said ester having the formula R,An, where An is an anion of a strong inorganic acid or an organic sulfonic acid, e.g., chloride, bromide, iodide, sulfate, methanesulfonate, benzenesulfonate, and para-toluensulfaonate. and R. is lower-alkyl. This alkylation is preferably run using a slight excess of the alkylating agent. The chloride, bromide or iodide is preferred because of the ready availability of the requisite loweralkyl halides; and the reaction is carried out preferably in the presence of an acid-acceptor. The acidacceptor is a basic substance which preferably forms freely water-soluble by-products easily separable from the product of the reaction, including for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium alkoxides, potassium alkoxides, sodium amide, and the like. The acid-acceptor takes up the hydrogen halide (or I-IAn) which is split out during the course of the reac- 7 tion and also takes up the proton from the l-position of IV or from the 4-OH of IVA to generate the resulting anion of IV or IVA. The reaction can be carried out in either the presence of absence of a suitable solvent, but preferably in a solvent such as lower-alkanol, acetone, dioxane, dimethyl-formamide, dimethyl sulfoxide, hexamethyl phosphoramide, or a mixture of solvents, e.g., a mixture of water and a loweralkanol. The reaction is generally carried out at a temperature between about room temperature (about 20-25C.) and C, preferably heating on a steam bath in a stirred mixture of dimethylformamide and anhydrous potassium carbonate.

The conversion of 3-acetyl-l-(lower-alkyl)-1,4-dihydro-7-Q-4-oxol ,8-naphthyridine-3-carboxylic acid (VI) is carried out by treating V with an agent capable of converting COCI-I to COOI-I. This is conveniently done by reacting V with chlorine or bromine and an alkali metal hydroxide, preferably sodium or potassium hydroxide, or the corresponding alkali hypohalite. This conversion of V to VI also can be carried out by reaction V with iodine and pyridine followed by reacting the resulting COCI-I I-I lwith alkali, e.g., aqueous sodium or potassium hydroxide solution; the reaction with the iodine and pyridine is conveniently carried out by heating the reaction mixture on a steam bath and the reaction of the resulting pyridinium'iodide compound is conveniently hydrolyzed in refluxing aqueous sodium or potassium hydroxide solution. Alternatively, the conversion of V to VI is carried out by reacting V with a mixture of potassium or sodium hydroxide and carbon tetrachloride, preferably at about 2580C. with stirring in a suitable aqueous solvent, e.g., water and a lower-alkanol, e.g., t-butanol. Also, the conversion of V to VI is carried out by heating V with dilute aqueous nitric acid, preferably refluxing 20% nitric acid.

The reaction of lower-alkyl a-(6-methyl-2- pyridylaminomethylene)acetoacetate (III) or 3-acetyl- 1,4-dihyd ro-7-methyl-4-oxo-l ,8-naphthyridine (IV) or its tautomer (IVA) with an oxidizing agent to form, respectively, lower-alkyl a-( 6-methyl-l-oxo-2- pyridylaminomethylene)acetoacetate or 3-acetyl-l,4- dihydro-7-methyl-4-oxo- 1 ,8-naphthyridine-8-oxide or its tautomeric -8-oxide is carried out by reacting III or 5 IV(or IVA) with an oxidizing agent capable of forming N-oxides, preferably with a per acid, e.g., peracetic acid, perbenzoic acid, 3-chloroperbenzoic acid, and the like, or with other oxidizing agents, e.g., hydrogen peroxide, in the presence of a suitable inert solvent, e.g., acetic acid, chloroform, and the like. The reaction is conveniently run by mixing the reactants carefully at room temperature (about 2025C.) up to about 4050C., preferably with stirring, and then heating the reaction mixture on a steam bath to ensure completion of the reaction.

The conversion of lower-alkyl a-(6-methyl-l-oxo-2- pyridylaminomethylene)acetoacetate or 3-acetyl-l,4- dihydro-7-methyl-4-oxo- 1 ,8-naphthyridine-8-oxide (or tautomer) to the corresponding lower-alkyl a-[6-(lower-alkanoyloxymethyl )-2-pyridylaminomethylene acetoacetate or 3'acetyl-l,4-dihydro- 7-(loweralkanoyloxymethyl)-4oxo-1,8-naphthyridine (or tautomer), respectively, is carried out by reacting the 6- methyl-l-oxo-Z-pyridyl compound or -8-oxide with a loweralkanoic acid anhydride. The reaction is conveniently run using as solvent an excess of the anhydride or the corresponding alkanoic acid, e.g., acetic acid with acetic anhydride, or any suitable solvent unreactive to said anhydrides, e.g., acetonitrile, benzene, toluene, dimethylformamide, and the like. This reaction is generally carried out in the range of about 70l50C., preferably on a steam bath.

The best mode contemplated for carrying out the invention is now set forth as follows:

EXAMPLE 1 Ethyl a-( 6-methyl-2-pyridylaminomethylene )acetoacetate To a solution containing 21.6 g. of 2-amino-6- methylpyridine in 100 ml. of ethanol was added with stirring 38 g. of ethyl ethoxymethyleneacetoacetate whereupon an exothermic reaction ensured causing the solution to warm up to about 67C. After being allowed to stand for about minutes, the reaction mixture was heated on a steam bath for minutes, diluted to a volume of about 200 ml. with ethanol, allowed to cool and chilled. The resulting crystalline precipitate was collected, washed with cold ethanol, and dried in vacuo at 50C. to yield 6.5 g. of white crystalline ethyl a-( 6- methyl-2-pyridylaminomethylene)acetoacetate, m.p. 9910lC.

Following the procedure described above in Example 1 but using in place of ethyl ethoxymethyleneacetoacetate a molar equivalent quantity of the appropriate lower-alkyl (lower-alkoxy) methyleneacetoacetate, there are obtained: methyl rx-( 6-methyl-2-pyridylaminomethylene)acetoacetate using methyl methoxymethyleneacetoacetate; n-propyl a-( 6-methyl-2 -pyridylaminomethylene)acetoacetate using n-propyl n-propoxymethyleneacetoacetate; isobutyl a-(6-methyl-Z-pyridylaminomethylene)acetoacetate using isobutyl ethoxymethyleneacetoacetate; n-hexyl a-( 6-methyl- 2-pyridylaminomethylene)acetoacetate using n-hexyl n-hexoxymethyleneacetoacetate; and isopropyl a-(6- methyl-2-pyridylaminomethylene) acetoacetate using isopropyl isopropoxymethyleneacetoacetate.

EXAMPLE 2 3-Acetyll ,4-dihydro-7-methyl-4-oxo-1,S-naphthyridine A mixture containing 34.5 g. of ethyl oz-(6-methyl-2- pyridylaminomethylene)acetoacetate and 700 ml. of mineral oil was heated with stirring to a temperature of 300C, kept at 300C. for about 30 seconds and allowed to cool with stirring to about C. The precipitate was collected, triturated with hot n-hexane and crystallized from dimethylformamide to yield 9.0 g. of 3-acetyl-l ,4-dihydro-7-methyl-4-oxol ,S-naphthyridine, m.p. 326329C. A sample was purified for analysis by dissolving it in 10 percent aqueous potassium hydroxide solution, boiling the solution for about 2 minutes, neutralizing it with hydrochloric acid, and collecting the product, m.p. 338-340C. A mixed melting point with the original material melting at 326-329C. showed no depression.

The above cyclization of ethyl a(6-methyl-2- pyridylaminomethylene)acetoacetate to produce 3- acetyl-l ,4-dihydro-7-methyl-4-oxol ,S-naphthyridine also was carried out in refluxing Dowtherm A (eutectic mixture of diphenyl and diphenyl ether) for one hour and by heating it in diethyl phthalate at 290C. for about 5 to 10 minutes.

3-Acetyll ,4dihydro-7-methyl-4-oxol ,8-naphthyridine also is produced by following the above-described procedure but using in place of ethyl a-(6-methyl-2- pyridylaminomethylene)acetoacetate a molar equivalent quantity of other lower-alkyl a-(6-methyl-2- pyridylaminornethylene)acetoacetates, e.g., methyl, n-propyl, isopropyl, isobutyl or n-hexyl a-(6-methyl-2- pyridylaminomethylene acetoacetate EXAMPLE 3 urated with warm water, washed sparingly with acetone and dried at 60C. in vacuo to yield 13.2 g. of 3-acetyll-ethyll ,4-dihydro-7-methyl-4-oxol ,S-naphthyridine, m.p. l79-l8lC.

' EXAMPLE 4 1-Ethyll ,4-dihydro-7-methyl-4oxol ,8-naphthyridine-3-carboxylic acid To a stirred solution kept at 0l0C. and containing 33 g. of sodium hydroxide (98 percent) in 280 ml. of water is added over a period of 15 minutes 48 g. of bromine. To this solution is added 23 g. of 3-acetyl-lethyl l ,4-dihydro-7-methyl-4-oxo-l ,8-naphthyridine and the resulting reaction mixture is stirred for one hour at 0-l0C., for 6 hours at room temperature (about 2025C.) and for 30 minutes on a steam bath. The hot reaction mixture is filtered and the filtrate is acidified with aqueous hydrochloric acid to precipitate '7 the product. The precipitate is collected and recrystallized from acetonitrile to yield l-ethyl-l,4-dihydro-7- methyl-4-oxo-1 ,8-naphthyridine-3-carboxylic acid, m.p. 228230C.

The conversion of 3-acetyl-1-ethyl- 1 ,4-dihydro-7- methyl-4-oxol ,8-naphthyridine to l-ethyl-l ,4-dihydro-7-methyl-4-oxo-1 ,8-naphthyridine-3-carboxylic acid also is carried out alternatively as follows: by warming on a steam bath for ninety minutes a mixture containing 2.42 g. of 3-acetyl-1-ethyl-1,4-dihydro-7- methyl-4-oxo-1,8-naphthyridine, 4.8 ml. of pyridine and 1.72 g. of iodine, allowing the reaction mixture to stand overnight at room temperature, removing the excess pyridine in vacuo, drying the residue in vacuo at 130C., heating the residue under reflux for one hour in 70 ml. of l N potassium hydroxide solution in diethylene glycol which contained 2 ml. of water, diluting the solution with water, acidifying the solution with hydrochloric acid, extracting the mixture with ether, extracting the product from the ether with dilute sodium bicarbonate, decolorizing the resulting aqueous solution with decolorizing charcoal, acidifying the resulting solution and collecting the crystalline 1-ethyl1,4-dihydr-7-methyl-4-oxol ,8-naphthyridine-3-carboxylic acid.

Another conversion of said 3-acetyl compound to the 3-carboxy compound is carried out by heating a mixture containing 1 g. of the 3-acetyl compound, 4 g. of powdered potassium hydroxide, 5 ml. of t-butanol, 3 ml. of water and ml. of carbon tetrachloride at 6070C. for 45 minutes, and then working up the reaction mixture as in the'preparation given in the immediately preceding paragraph.

In another conversion of the 3-acetyl compound to l-ethyl-l ,4-dihydro-7-methyl-4-oxo-1 ,8-naphthyridine-3-carboxylic acid, a 2.32 g. portion of said 3- acetyl compound is refluxed for five hours with 70 ml. of percent nitric acid, the reaction mixture is evaporated to dryness in vacuo, the residue is boiled for fifteen minutes with acetic acid, the the separated 3-carboxylic acid is collected and recrystallized from acetonitrile.

Following the procedures described in Example 1 but using in place of 2-amino-6-methylpyridine a molar equivalent quantity of the appropriate 2-amino-6-Q- pyridine, the compounds of Examples 5-9 and 14-21 are obtained:

EXAMPLE 5 Ethyl a( 6-ethyl-2-pyridylaminomethylene )acetoacetate using 2-amino-6-ethylpyridine.

EXAMPLE 6 Ethyl a-( 6-n-propyl-2-pyridylaminomethylene )acetoacetate using 2-amino-6-n-propylpyridine.

EXAMPLE 7 Ethyl a-( 6-isobutyl-2-pyridylaminomethylene )acetoacetate using 2-arnino-6isobutylpyridine, the later prepared by reacting 2-isobutylpyridine with sodamide.

EXAMPLE 8 Ethyl ct-(6-n-hexyl-2-pyridylaminomethylene)acetoacetate using Z-amino-6-n-hexylpyridine, the latter prepared by reacting 2-n-hexylpyridine with sodamide.

EXAMPLE 9 Ethyl a-( 6-hydroxymethyl-2-pyridylaminom ethylene)acetoacetate using 2-amin0-6-hydroxymethylpyridine, which is prepared by reacting 2-acetylamino- 6-methylpyridine-l-oxide with acetic anhydride and hydrolyzing with aqueous potassium hydroxide solution the resulting 6-acetoxymethyl-2-acetylaminopyridine to remove both the O-acetyl and N-acetyl groups.

EXAMPLE 1O EXAMPLE 1 1 Ethyl a-( 6-propionoxymethyl-2-pyridylaminomethylene)acetoacetate is prepared as in Example 10 but using propionic anhydride instead of acetic anhydride in each instance.

EXAMPLE l2 Ethyl oz-(6-isobutyroxymethyl-2-pyridylaminomethylene)acetoacetate is prepared as in Example 10 but using isobutyric anhydride instead of acetic anhydride in each instance.

EXAMPLE 13 Ethyl a-(6-hexanoyloxymethyl-2-pyridylaminomethylene )acetoacetate is prepared as in Example 10 but using hexanoic acid anhydride instead of acetic anhydride in each instance.

EXAMPLE 14 Ethyl a- 6-( 4-pyridyl )-2-pyridylaminomethylene ]acetoacetate using 2-amino-6-(4-pyridyl)pyridine.

EXAMPLE 15 Ethyl a-[ 6-( 3 -pyridyl )-2-pyridylaminomethylene]acetoacetate using 2-amino-6-(3-pyridyl)pyridine.

EXAMPLE 16 Ethyl a- 6-( 2-methyl-4-pyridyl -2- pyridylaminomethylene]acetoacetate using 2-amino-6- (2-methyl-4-pyridyl)pyridine.

EXAMPLE l7 Ethyl a- 6-( 3-methyl-4-pyridyl -2- pyridylaminomethylene acetoacetate using 2-amino-6- (3-methyl-4-pyridyl )pyridine.

EXAMPLE l8 Ethyl a-[ 6-( 2-ethyl-4-pyridyl )-2-pyridylaminomethylenelacetoacetate using 2-amin0-6-(2-ethyl-4-pyridyl)- pyridine.

EXAMPLE l9 Ethyl oz-[ 6-( 3-ethyl-4-pyridyl )-2-pyridylaminomethylene]acetoacetate using 2-amino-6-( 3-ethyl-4-pyridyl pyridine.

EXAMPLE 2O Ethyl a-[6-(2,6-dimethyl-4-pyridyl)-2- pyridylaminomethylene]acetoacetate using 2-amino-6- (2,6-dimethyl-4-pyridyl)pyridine.

EXAMPLE 21 Ethyl a-[6-(3,5-dimethyl-4-pyridyl)-2- pyridylaminomethylene]acetoacetate using 2-amino-6- 3 ,5-dimethyl-4-pyridyl )pyridine.

Following the procedure described in Example 2 but using in place of ethyl a-(6-methyl-2-pyridylaminomethylene)acetoacetate a molar equivalent quantity of the appropriate ethyl a-(6-Q-2-pyridylaminomethylene)acetoacetate, the compounds of Examples 22-38 are obtained:

EXAMPLE 22 3-Acetyl-7-ethyll ,4-dihydro-4-oxol ,8-naphthyridine using ethyl a-(6-ethyl-2-pyridylaminome thylene)acetoacetate.

EXAMPLE 23- 3-Acetyl-l ,4-dihydro-4'oxo-7-npropyl-l ,8-naphthyridine using ethyl a-( 6-n-propyl-2-pyridylaminomethylene)acetoacetate.

EXAMPLE 24 3-Acetyll ,4-dihydro-7-isobutyl-4-oxol ,8-naphthyridine using ethyl oz-(6-isobutyl-2-pyridylaminome thylene)acetoacetate.

EXAMPLE 25 3-Acetyl7-n-hexyl-l ,4-dihydro-4-oxol ,8naphthyri dine using ethyl a-(6n-hexyl-2-pyridylaminomethylene)acetoacetate.

EXAMPLE 26 3-Acetyl-l ,4-dihyro-7-hydroxymethyl-4-oxo-1 ,8- naphthyridine using ethyl a-(6-hydroxymethyl-2- pyridylaminomethylene)acetoacetate.

EXAMPLE 27 7-Acetoxymethyl-3-acetyll ,4-dihydro-4-oxol ,8- naphthyridine using ethyl a-(6-acetoxymethyl-2- pyridylaminomethylene)acetoacetate. Alternatively, 7-acetoxymethyl-3-acetyll ,4-dihydro-4-oxo-l ,8-naphthyridine is prepared by reacting 3-acetyl-l,4-dihydro- 7-methyl-4-oxo-l,8-naphthyridine with peracetic acid to form its 8-oxide and reacting the 8-oxide with acetic anhydride.

EXAMPLE 28 3-Acetyll ,4-dihydro-4-oxo-7-propionoxymethyl- 1,8-naphthyridine using ethyl a-(6-propionoxymethyl- 2-pyridylaminomethylene)acetoacetate. Alternatively, 3-acetyl l ,4-dihydro-4-oxo-7-propionoxymethyl-1,8- naphthyridine is prepared by reacting 3-acetyl-1,4- dihydro-7-methyl-4-oxo-l,8-naphthyridine with peracetic acid to produce its 8-oxide and reacting the 8- oxide with propionic anhydride.

EXAMPLE 29 3-Acetyll ,4-dihydro-7-isobutyroxymethyl-4-oxol,8-naphthyridine using ethyl a-(6-isobutyroxymethyl- 2-pyridylaminomethylene)acetoacetate. Alternatively, 3-acetyll ,4-dihydro-7-isobutyroxymethyl-4-oxol ,8- naphthyridine is prepared by reacting 3acetyl-l,4-

10 dihydro-7-methyl-4-oxo-l,8-naphthyridine with peracetic acid to produce its 8-oxide and reacting the 8- oxide with isobutyric anhydride.

EXAMPLE 3O 3-Acetyl-7-hexanoyloxymethyll ,4-dihydro-4-oxo- 1,8-naphthyridine using ethyl a-( 6-hexanoyloxymethyl Z-pyridylaminomethylene acetoacetate. Alternatively, 3-acetyl-7-hexanoyloxymethyl- 1 ,4-dihydro-4-oxol ,8- naphthyridine is prepared by reacting 3-acetyl-1,4- dihydro-7-methyl-4-oxo-1,8-naphthyridine with peracetic acid to produce its 8-0xide and reacting the 8- oxide with hexanoic acid anhydride.

EXAMPLE 31 3-Acetyll ,4-dihydro-4-oxo-7-(4-pyridyl)-1,8-naphthyridine using ethyl a- 6-( 4-pyridyl -2- pyridylaminomethylene acetoac etate.

EXAMPLE 32 3-Acetyll ,4-dihydro-4-oxo-7-(3-pyridyl)-1 ,8-nap hthyridine using ethyl a-[6-( 3-pyridyl -2- pyridylaminomethylene acetoacetate.

EXAMPLE 33 3-Acetyll ,4-dihydro-7-( 2-methyl-4-pyridyl )-4-ox0- 1,8-naphthyridine using ethyl a-[6-(2-methyl-4- pyridyl)-2-pyridylaminomethylene]acetoacetate.

EXAMPLE 34 3-Acetyll ,4-dihydro-7-( 3-methyl-4-pyridyl-4-oxo- 1,8-naphthyridine using ethyl a-[6-(3-methyl-4- pyridyl)-2-pyridylaminomethylene]acetoacetate.

EXAMPLE 38 3-Acetyll ,4-dihydro-7-( 3 .5-dimethyl-4-pyridyl )-4- 0x0 1 ,S-naphthyridine using ethyl oz-[ 6-(3,5-dimethyl)- 4-pyridyl )-2-pyridylaminomethylene] acetoacetate.

Following the procedure described in Example 3 but using in place of 3-acetyl-l,4-dihydro-7-methyl-4-oxo- 1,8-naphthyridine a molar equivalent quantity of the appropriate 3-acetyl-l ,4-dihydro-4-o xo-7-Q-l ,S-naphthyridine, the compounds of Examples 39-55 are obtained:

EXAMPLE 39 3-Acetyll ,7-diethyl-l ,4-dihydr0-4-oxo- 1 ,S-naphthyridine using 3-acetyl-7-ethyl-l,4-dihydro-4-oxo-l ,8-

naphthyridine. Similarly, using said 7-ethyl compound and a molar equivalent quantity of dimethyl sulfate, npropyl iodide, isobutyl bromide or n-hexyl chloride in UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,925,398 DATED December 9, 1975 IN VENTOR(S) George Y. Lesher and Ruth Pauline Brundage It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

. Column 1, line 36 "pyridylaminomethyleneacetoacetate" should read pyridylaminomethylene)acetoacetate Column 2, .line 1, "7-Q4-" should read 7-Q-4- v Column 4, line 15, "toluensulfaonate" should read toluenesulfonate Column 4, line 44, following "l,8naphthyridine" Q insert (V) to l-(lower-alkyl) -l,4dihydro-7Q-4-oxo-l,8

naphthyridine Colu 4, line 52, "-COCH H l should read u COCH @QC H NCS 5 Column 16, line 5, "7Q-4" should read 7-Q-4 Signed and Scaled this 0 Twenty-fourth D3) of August 1976 [SEAL] Arrest.

g v RUTH C. MASON c. MARSHALL DANN' I I Arresting Officer Commissioner oj'larenrs and Trademarks 

1. A COMPOUND SELECTED FROM 3-ACETYL-1,4-DIHYDRO-7-Q-4OZO-1,8-NAPHTHYRIDINE AND ITS TAUTOMERIC 3-ACETYL-4-HYDROXY7-Q-1,8-NAPTHYRIDINE, WHERE Q IS LOWE-ALKYL, LOWERALK ANOYLOXMETHYL, HYDROXMETHYL, 4(OR 3)-PYRIDYL OR 4(OR 3)PYRIDYL HAVING ONE OR TWO LOWER-ALKYL SUBSTITUENTS.
 2. The compound according to claim 1 where Q is methyl.
 3. 3-Acetyl-1-(lower-alkyl)-1,4-dihydro-7Q-4-oxo-1,8-naphthyridine, where Q is lower-alkyl, hydroxymethyl, lower-alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)-pyridyl having one or two lower-alkyl substituents.
 4. 3-Acetyl-1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine according to claim
 3. 